Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center

After its initial publication in the 1950s,

 the use of whole-brain radiation therapy (WBRT) for patients with brain metastases became the treatment of choice for this population given its wide availability, ease of delivery, and effectiveness in providing palliation. In addition, the historically poor outcomes for the vast majority of patients with brain metastases fostered the routine use of WBRT and promulgated the nihilistic view that toxicities related to WBRT were inconsequential given the dismal outcomes and lack of effective systemic therapies for patients with extracranial metastases.

Currently, the major treatment alternative to WBRT is stereotactic radiosurgery (SRS), which allows for the delivery of precisely focused, highly targeted radiation to multiple intracranial tumors. In addition, SRS has distinct advantages over surgical resection, including the ability to treat multiple and deep-seated intracranial lesions in an outpatient setting.

Now, based on randomized phase III studies demonstrating superior neurocognitive preservation and duration of functional independence without the addition of WBRT to SRS,

 the adoption of SRS alone has greatly escalated and has become the standard primary and adjuvant treatment of choice at many medical centers. As part of its Choosing Wisely campaign, the American Society of Radiation Oncology (ASTRO) has recommended against the routine addition of adjuvant WBRT to SRS for patients with limited brain metastases.

However, despite the fervent advocacy of SRS alone, the addition of WBRT clearly improves local control, decreases distant brain failure, minimizes the need for salvage therapies such as surgery, and, most importantly, decreases neurologic death.

Yet, given the growing data against WBRT, one may question whether this therapy should be abandoned as an antiquated and toxic treatment for the majority of patients with brain metastases. Alternatively, novel approaches may potentially mitigate the neurocognitive toxicities of WBRT, which would support its role as a valuable treatment modality.

Two recent clinical trials, RTOG 0614 and RTOG 0933, provide some insight on how one can improve the therapeutic ratio of WBRT.

This phase III trial randomized 554 patients to WBRT with or without memantine, an N-methyl- D-aspartate receptor antagonist traditionally used for mild-to-moderate dementia in patients with Alzheimer disease.6 The trial tested the hypothesis that memantine could act as a neuroprotectant by minimizing the neurocognitive effects of WBRT.

Results from the study demonstrated less decline in the Hopkins Verbal Learning Test Revised Delayed Recall (HVLT-R DR) in the memantine arm (

 = .059). Although this difference was not statistically significant, which was possibly a result of only 35% statistical power given the limited number of analyzable patients at 24 weeks, the memantine arm was nevertheless associated with superior cognition over time, with delayed time to cognitive decline and reduced rates of decline in memory, executive function, and processing speed.

Based on the hypothesis that injury to the neural stem cells of the subgranular zone of the hippocampal dentate gyrus leads to the early cognitive decline following radiation therapy in preclinical studies, modern radiation planning techniques were explored to minimize exposure to this compartment of the hippocampus.

The RTOG 0933 study was a phase II trial of hippocampal avoidance (HA) WBRT intended to reduce the long-term effects of WBRT on neurocognition. 

 The primary endpoint of the trial was the HVLT-R DR at 4 months using a historical control from a comprehensive radiation sensitizer study in which patients received conventional WBRT.

To facilitate high-quality assurance, central rapid review was conducted in real time to ensure that stringent planning and contouring guidelines were followed.

Four months after HA-WBRT, 42 of the 100 analyzable patients had a 7% decline from baseline compared with a 30% mean relative HVLT-R DR decline in the historical control group (

To corroborate the results of RTOG 0933 and RTOG 0614, 2 cooperative group trials are ongoing. The first study, NRG-CC003, is a randomized phase II/III trial of prophylactic cranial irradiation (PCI) with or without HA-WBRT (2500 cGy in 10 fractions) for patients with extensive and limited-stage small cell lung cancer who achieve a complete or partial response to chemotherapy. The primary hypothesis for this trial is that HA-WBRT will decrease the 6-month HVLT-DR deterioration rate compared with standard PCI.

 The second study, NRG-CC001, is a randomized phase III trial of WBRT (3000 cGy in 10 fractions) plus memantine versus HA-WBRT (3000 cGy in 10 fractions) plus memantine for patients with brain metastases other than small cell lung cancer or germ cell malignancy. The primary objectives are to determine whether the addition of HA-WBRT increases the time to neurocognitive decline at 2, 4, 6, and 12 months based on a battery of neurocognitive tests.

Despite the mounting evidence against the routine use of WBRT, completed and ongoing clinical trials will help corroborate whether HA-WBRT is worth the extra time, resources, cost, and effort. Ultimately, the discovery of a reliable biomarker that correlates with the toxicities of WBRT and SRS would assist in the judicious use of either modality.

Moreover, better understanding of the influence of tumor biology on the development of brain metastases, toxicities associated with WBRT and SRS, and response to therapy will help further personalize treatment options and improve outcomes. Given the ongoing debate regarding the optimal management strategy for brain metastases, all patients should be evaluated in a multidisciplinary setting to determine the most appropriate treatment approach while we await results of the ongoing clinical trials.

Chao JH, Phillips R, Nickson JJ. Roentgen-ray therapy of cerebral metastases. 

Suh JH. Stereotactic radiosurgery for the management of brain metastases. 

Chang EL, Wefel JS, Hess KR, et al: Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. 

Kocher M, Soffietti R, Abacioglu U, et al: Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. 

American Society for Radiation Oncology. ASTRO releases second list of five radiation oncology treatments to question, as part of national Choosing Wisely® campaign. Choosing Wisely website. http://www.choosingwisely.org/astro-releases-second-list/. Published September 14, 2014. Accessed May 28, 2016.

Brown PD, Pugh S, Laack NN, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. 

Gondi V, Tomé WA, Mehta MP. Why avoid the hippocampus? A comprehensive review. 

Gondi V, Tolakanahalli R, Mehta MP, et al. Hippocampal-sparing whole-brain radiotherapy: a "how-to" technique using helical tomotherapy and linear accelerator-based intensity-modulated radiotherapy.

Gondi V, Pugh SL, Tome WA, et al. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. 

Mehta MP, Rodrigus P, Terhaard CHJ, et al. Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. 

Articles

Despite the fervent advocacy of stereotactic radiosurgery alone, the addition of whole-brain radiation therapy clearly improves local control, decreases distant brain failure, minimizes the need for salvage therapies such as surgery, and, most importantly, decreases neurologic death.

John H. Suh, MD

Articles

The Jury's Still Out on Whole-Brain Radiation Therapy for Brain Metastases